Structure and Function of Pentameric Ligand-gated Ion Channels

Case Western Reserve University, Cleveland OH

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Abstract

PROJECT SUMMARY/ABSTRACT The overarching objectives of this research program are to determine the molecular basis of allosteric mechanisms that govern gating and modulation in pentameric ligand-gated ion channels (pLGICs). The pLGIC superfamily governs crucial physiological processes such as gastrointestinal functions, motor coordination, and pain transmission. Aberrant channel functions are implicated in neurological disorders, addiction, and chronic pain. Currently used therapeutic strategies suffer from our limited knowledge of pLGIC assemblies in their native environment, the origin of their functional diversity, and the downstream regulatory events. Over the last five years, we have made significant discoveries in two pLGIC members- serotonin (3) receptor (5HT3R), an excitatory channel, and glycine receptor (GlyR), an inhibitory channel. We have determined molecular details of neurotransmitter recognition, channel gating, desensitization, and drug modulation. Building on these advancements, we will probe the architecture and functional mechanisms in heteromeric pLGIC assemblies and dig deeper into their post-translational regulation and functional interactomes comprising of synaptic binding partners. To achieve these goals we will use cutting-edge multidisciplinary techniques, including cryo-electron microscopy (cryo-EM), protein dynamics measurements, mass spectrometry, molecular dynamic simulations, and electrophysiology. Taken together, our proposed work is expected to provide molecular blueprints of the channel in physiologically relevant conformations for therapeutic targeting and unravel mechanisms underlying channel function. These findings will in turn pave the way for the design of novel therapeutic agents that are safer and more effective.